Regulation of Excitability in the Epileptic Human Dentate Gyrus

Abstract

Numerous anatomical and physiological changes occur in the dentate gyrus of patients with medial temporal lobe sclerosis, a specific form of temporal lobe epilepsy. Although many of the reported changes are potentially proconvulsive, patients do not seize continuously. We hypothesize that neuromodulatory systems present in the epileptic dentate gyrus may help limit neuronal hyperexcitability and/or hypersynchronization. Three such systems are described in detail, including GABA, zinc, and adenosine. In addition, we briefly discuss several other modulatory systems that have not been studied extensively in the epileptic human hippocampus but that are also well suited to controlling neuronal excitability. NEUROSCIENTIST 5362- 370, 1999 Seizure disorders are among the most common and devastating neurological problems. Approximately 5% of the U.S. population that live to the age of 80 have a seizure disorder at some point in their lives (1). Epilepsy can result from a great diversity of underlying causes and its clinical manifestations can vary greatly based on the underlying etiology (e.g., tumors, trauma, or developmental anomalies) and on the cortical region involved. Medial temporal lobe epilepsy (TLE) is probably the most commonly studied of all the epilepsies, primarily because of the stereotyped pattern of clinical and pathological findings seen in patients with a subclass of TLE, medial temporal lobe sclerosis (MTS), and the inability to successfully treat these patients with the available antiepileptic compounds. MTS is a pathological definition first described in 1966 (2) and is characterized by extensive (6040%) cell loss in the CA1 and CA3 regions of the hippocampus and within the dentate hilus. Human MTS tissue has since been studied using a variety of techniques. These studies have been aided by the extensive body of literature on the anatomy and physiology of the rodent hippocampal formation.Clinically, MTS patients present with medically intractable seizures of temporal lobe origin. Its clinical evaluation has been described by a number of authors (3) and includes quantitative MRI analysis, neuropsychological evaluation for lobar-specific deficits, and continuous audio-visual EEG monitoring. The "classical" yalexdu).MTS patient has a history of neurological insult during childhood, often a febrile seizure, followed by a seizurefree period that can last for up to a decade, and the subsequent development of progressively intractable seizures. In general, MRI scans show unilateral hippocampal and temporal lobe atrophy on the side of seizure onset as determined by EEG analysis, with no evidence for structural lesions. Neuropsychological assessment shows that there are specific memory and functional deficits associated with MTS that also correlate to the side of seizure onset (4). When this constellation of clinical findings is present, anteromedial temporal lobectomy with hippocampectomy is associated with an 80 to 90% seizure-free outcome (5).A variety of structural lesions within the temporal lobe, in...

Aging Alters Electroencephalographic and Clinical Manifestations of Kainate‐induced Status Epilepticus

“…Changes in extralimbic areas also are likely to occur during aging, because a shorter latency to onset for convulsive seizures and sustained convulsive seizures was noted. Furthermore, data suggest that neuromodulatory systems may be altered during aging (38,50–52), and these systems have been shown to regulate epileptiform activity in vitro, as well as seizure severity/susceptibility and spread in vivo (53–56). However, the possibility cannot be discounted that aging‐related changes in peripheral organs (e.g., renal clearance), the blood–brain barrier, and/or pharmacokinetics also are involved with producing the altered EEG and behavioral characteristics in aged rodents during kainate‐induced status epilepticus.…”

Book Review: GABA and Glutamate in the Human Brain

“…Having a strong zinc chelator at the GABA receptor should enhance the inhibitory action of GABA, particularly at those GABA receptors expressing the gamma-subunit (Smart and others 1994;Buhl and others 1996). Zinc also synchronizes release of GABA and modulates glutamatergic receptors (Williamson and Patrylo 1999). Thus, homocarnosine can modulate neuronal excitability through a number of mechanisms.…”

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“…Better seizure control was associated with higher homocarnosine levels in all patients (CPS and JME) taking valproate or lamotrigine. [58][59][60] Zinc also synchronizes release of GABA and modulates glutamatergic receptors. It may interact directly with GABA receptors or after hydrolysis to GABA and histidine.…”

“…Homocarnosine is a dipeptide with anticonvulsant properties with several potential mechanisms of action. 58,59 Thus homocarnosine can modulate neuronal excitability through a number of mechanisms. 21 A specific enzyme, homocarnosinase (human serum carnosinase), rapidly hydrolyzes homocarnosine.…”